Genomic landscape of acquired resistance to targeted therapies in metastatic colorectal cancer (mCRC).
Authors: Emily Harrold, Fergus Keane, Jenna Cohen Sinopoli, Luis A. Diaz, Andrea Cercek, Rona Yaeger
Journal: Journal of Clinical Oncology (2023)

190 Background: Therapies targeting oncogenic driver mutations have radically altered the treatment paradigm for mCRC and improved outcomes. New selective inhibitors aim to expand the portion of mCRC with targetable alterations. However, these drugs are limited by a relatively short duration of response before the emergence of acquired resistance. We hypothesized that both the putative resistance mechanism (mutations (MUT) versus copy number alterations (CNA)) and the clonality of the emergent mutations may influence time to resistance. Methods: We screened the MSKCC IMPACT dataset of 5,403 MSS (microsatellite stable) CRC patient samples (3,704 primary sequenced, 1669 metastatic site sequenced) for patients (pts) who had been treated with targeted therapies against EGFR, BRAF, KRAS G12C, or HER2 with tissue or liquid biopsy samples profiled at progression. Clinicopathological features and acquired genomic changes emerging at resistance were assessed. Results: 42 pts were identified with targeted oncogenic drivers consisting of BRAF V600E (17 pts), EGFR (12 pts), KRAS G12C (11 pts), and HER2 (2 pts). Progression specimens analyzed consisted of tissue biopsies in 17 pts (40%) and circulating free DNA (cfDNA) in 21 pts (50%), 4 pts had both tissue and cfDNA analyzed at progression. Median time on targeted therapy (TOT) was 7.1 months (95% CI: 5.6-8.5). Putative resistance alterations were identified in 33 pts (79%) (18 cfDNA, 11 tissue, 4 both cfDNA and tissue) and consisted of MUT alone in 30%, MUT+CNA or rearrangement 70%. Concurrent PIK3CA mutations in pre-treatment tissues were identified in 17 pts (40%) and did not associate with TOT (p=0.68); acquired PI3K pathway alterations were identified in 5 pts (12%), including 2 pts who had baseline tumor PIK3CA mutation. Number of putative resistance alterations ranged from 0-13, with multiple resistance alterations identified in 18 pts (15 ctDNA, 3 tissue), and these could be categorized into three groups: one alteration (15/33; 45%), 2-4 alterations (8/33; 24%), and ≥5 alterations (10/33; 30%). Evaluating TOT by type of alteration: MUT only: 9.8 months, MUT+ CNA+/- rearrangement: 6.6 months (p=0.0079). Evaluating TOT by number of alterations: &gt;4 alterations: 6.1 months versus 1-4 alterations: 8.9 months (p=0.012), or 1 alteration: 8.0 months versus &gt;1 alteration: 6.7months (p= 0.5). There was no significant difference in TOT when evaluating by clonality of mutations, where subclonal was defined as &lt;5% of highest variant allelic fraction (clonal vs subclonal, 9.7 vs 6.7 months, p= 0.09). Fusions identified at time of resistance (involving BRAF in 2 pts, MET in 1 pt, RET in 1 pt) occurred with ≥5 alterations in 3 of 4 pts. Conclusions: Presence of CNA and ≥5 new alterations at resistance were associated with shorter TOT, and there was a trend for subclonal alterations and shorter TOT. New approaches that target underlying mechanisms for these changes may extend TOT.